Inhibiting oxidative degradation of pharmaceutical formulations

ABSTRACT

The invention provides methods for inhibiting oxidative degradation of pharmaceutical formulations comprising at least one oxidation-susceptible active drug ingredient which methods comprise adding an oxidation-inhibiting amount of a ferrous ion source, preferably in the form of a pharmaceuticalexcipient, to the formulation.  
     The invention further provides pharmaceutical formulations comprising at least one oxidation-susceptible active drug ingredient and an oxidation-inhibiting amount of a ferrous iron source, preferably in the form of a pharmaceuticalexcipient.  
     The invention still further provides for the use of a ferrous ion source as an anti-oxidant in pharmaceutical formulations.

CROSS REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of U.S. ProvisionalApplication No. 60/188,447 filed Mar. 10, 2000.

BACKGROUND OF THE INVENTION

[0002] The invention relates to methods of inhibiting oxidativedegradation of pharmaceutical formulations comprising at least oneoxidation-susceptible active drug ingredient and to pharmaceuticalformulations comprising oxidation-inhibiting excipients.

[0003] The desirability of providing pharmaceutical formulations inwhich an oxidation-susceptible active drug ingredient or ingredients areprotected against oxidative degradation inherent to prolonged storage isa concept well known to, and appreciated by, one of ordinary skill inthe art. Anti-oxidants commonly employed in various pharmaceuticalformulations may include, inter alia, vitamin E, ascorbic acid, BHT(butylated hydroxytoluene), BHA (butylated hydroxyanisole), and thelike.

[0004] Pharmaceutical formulations comprising ferrous ion sources asnutritional supplements are generally well known in the art. Thepresence of ferrous ion sources in pharmaceutical formulations hasadditional utility in other capacities. For example, it has beenreported that preservation of oral liquid preparations from bacterialcontamination can be achieved by treatment with, inter alia, certainferrous sulfate/methylparaben mixtures. See H. van Doorne, et al.,Pharmacy World & Science, 16 (1), 18-21 (1994). It has also beenreported that the addition of ferrous salts to compositions comprisingacetylsalicylic acid, or salts thereof, reduces the propensity of thecompositions to induce gastric irritation. See A. Goudie, et al., U.S.Pat. No. 4,083,951.

[0005] The present invention discloses methods for protecting anoxidation-susceptible active drug ingredient or ingredients in apharmaceutical formulation from oxidative degradation which methodscomprise adding a ferrous ion source to the formulation, preferably inthe form of a pharmaceutical excipient comprising the formulationcomponents. In this manner, pharmaceutical formulations are produced inwhich the active drug ingredient or ingredients are protected fromoxidative degradation, thus facilitating storage of the formulation overextended periods of time.

SUMMARY OF THE INVENTION

[0006] The instant invention provides methods for inhibiting oxidativedegradation of pharmaceutical formulations comprising at least oneoxidation-susceptible active drug ingredient which comprises protectingthe formulation by the addition of an oxidation-inhibiting amount of aferrous ion source thereto, preferably in the form of a pharmaceuticalexcipient.

[0007] The invention further provides pharmaceutical formulationscomprising at least one oxidation-susceptible active drug ingredient andan oxidation-inhibiting amount of a ferrous iron source, preferably inthe form of a pharmaceuticalexcipient.

[0008] The invention still further provides for the use of a ferrous ionsource as an anti-oxidant in pharmaceutical formulations.

DETAILED DESCRIPTION OF THE INVENTION

[0009] The instant invention provides methods of inhibiting oxidativedegradation of pharmaceutical formulations comprising at least oneoxidation-susceptible active drug ingredient which methods compriseadding to the formulation an oxidation-inhibiting amount of a ferrousion source, preferably in the form of a pharmaceuticalexcipient.

[0010] The invention further provides pharmaceutical formulationscomprising at least one oxidation-susceptible active drug ingredient andan oxidation-inhibiting amount of a ferrous iron source, preferably inthe form of a pharmaceuticalexcipient.

[0011] The invention still further provides for the use of a ferrous ionsource as an anti-oxidant in pharmaceutical formulations.

[0012] As employed throughout the instant description and appendantclaims, the term “ferrous” denotes a salt comprising the element iron inits lowest valence state, i.e. Fe⁺².

[0013] According to the methods of the invention, a formulationcomprising at least one oxidation-susceptible active drug ingredient isprotected against oxidative degradation by the addition of anoxidation-inhibiting amount of a ferrous ion source thereto. Although abroad spectrum of pharmaceutical formulations comprising at least oneoxidation-susceptible active drug ingredient will benefit from theaugmented protection to oxidative degradation provided by the methods ofthe instant invention, formulations comprising an active ingredient oringredients incorporating at least one amine or benzyl functional groupare particularly benefited. Preferably, the ferrous ion source shouldbe, for purposes of penultimate formulation, substantially soluble inwater or a lower molecular weight alcohol, for example, methanol,ethanol, or isopropanol, and should also be chemically compatible withthe active drug ingredient or ingredients and any additional componentscomprising the formulation. The ferrous ion source comprising theformulation should also be toxicologically compatible with the subjectbeing treated. Accordingly, ferrous ion sources that are unstable,chemically incompatible with the active ingredient or ingredientscomprising the formulation, or toxicologically incompatible with thesubject being treated, are not preferred. Generally preferred ferrousion sources may comprise, for example, ferrous sulfate, ammonium ferroussulfate, ferrous chloride, ferrousgluconate, ferrous citrate, ferrousfumarate, ferrous lactate, ferrous carbonate, chelated and hydratedforms thereof, and mixtures thereof. Particularly preferred ferrous ionsources comprise those compounds selected from the group consisting offerrous sulfate, ammonium ferrous sulfate hexahydrate, and ferrouschloride. Ammonium ferrous sulfate hexahydrate is especially preferred.

[0014] Although the ferrous ion source and the active drug ingredient oringredients comprising the formulation may be compounded by simpleintimate admixture, it is generally preferred that the ferrous ionsource comprise at least a portion of a pharmaceutical excipient. Suchexcipients are well known to one of ordinary skill in the art and maycomprise, for example, dicalcium phosphate, sodium citrate, calciumcarbonate, microcrystalline cellulose, silicified microcrystallinecellulose, lactose, kaolin, mannitol, starch, sucrose, dextrose, and thelike. The excipient comprising the ferrous ion source may be prepared byconventional methods well known to one of ordinary skill in the art. Forexample, the excipient may be prepared by spraying or intimatelyadmixing a solution of the ferrous ion source at an appropriate ordesired concentration with the other components comprising theexcipient. Once the excipient comprising the ferrous ion source has beenuniformly admixed, for example, by mixing in a high shear mixer, it isdried thoroughly, for example, in a fluid bed dryer or an oven dryer.Preferably, the dried excipient is then passed through a mill or screento ensure that a uniform particle size has been achieved. Although theconcentration of the ferrous ion source may vary, it typically comprisesfrom about 0.001% to about 5.0% by weight of the formulation.Preferably, the concentration of the ferrous ion source comprises fromabout 0.002% to about 0.02% by weight, based upon the amount of theexcipient present in the formulation. For example, if a fomulationcontained 100 g of excipients, it would preferably contain about 1 mg toabout 5 g of ferrous ion source. An amount comprising about 0.01% byweight of the formulation is especially preferred. These amount rangesmay, of course, be varied somewhat according to the active drugingredient or ingredients to be stabilized as will be recognized andappreciated by one of ordinary skill in the art having benefit of theteachings of the instant disclosure. The ability to select anappropriate ferrous ion source as well as an effective amount thereof toprotect a particular pharmaceutical formulation comprising at least oneoxidation-susceptible active drug ingredient against oxidativedegradation according to the methods of this invention is within thepurview of one of ordinary skill in the art having the benefit of theinstant disclosure.

[0015] Generally, methods of preparing solid dosage formulationscomprising an active ingredient or ingredients and a pharmaceuticalexcipient are well known, or will be readily apparent in light of theinstant disclosure, to of one of ordinary skill in the art. See, forexample, Remington's Pharmaceutical Sciences, Mack Publishing Company,Easton, Pa., 18th Edition (1990). The pharmaceutical formulations ofthis invention may comprise any conventional solid dosage formincluding, for example, tablets, pills, capsules, and the like. Theformulations may further comprise a binder such as hydroxypropylmethylcellulose, gum tragacanth, acacia gum, corn starch or gelatin; adisintegrating agent such as corn starch, potato starch,alginic acid,sodium starch gylcolate, croscamellose sodium, or crospovidone; alubricant such as magnesium stearate; and a sweetening agent such assucrose, lactose, or saccharin. Various other materials may be presentin the form of coatings or to modify the physical form of the dosageunit. For instance, tablets may be coated with mixtures comprising, forexample, titanium dioxide, dextrose, polyethylene glycol, sodiumcarboxymethyl cellulose, dextrin, and the like. The coatings may alsocomprise the form of an enteric polymer including phthalate derivatives,such as cellulose acetate phthalate, polyvinylacetate phthalate andhydroxypropylmethyl cellulose phthalate, polyacrylic acid derivatives,such as methacrylic acid copolymer, vinyl acetate, and crotonic acidcopolymers.

[0016] It is to be understood that the examples of the invention setforth hereinbelow are not to be construed as limitations thereof, asadditional embodiments within the scope of the appendant claims will beknown, or apparent in light of the instant disclosure, to one ofordinary skill in the art.

EXPERIMENTAL

[0017] The compound(2S,3S)-N-(5-isopropyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-amine,to be referred to hereinafter as Compound 1, prepared as described inU.S. Pat. No. 5,807,867; and the tartrate salt of the compoundcis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol(lasofoxifene tartrate), to be referred to hereinafter as Compound 2,prepared as described in U.S. Pat. No. 5,552,412. were formulated intosolid dosage formulations as described hereinbelow.

[0018] Compound 1 was formulated with, inter alia, excipients comprisingabout 0.01% by weight of ammonium ferrous sulfate hexahydrate into solidbinary pharmaceutical formulations as follows. A solution of 350 mg offerrous ammonium sulfate hexahydrate, dissolved in 100 ml of pure water,was added to 500 g of microcrystalline cellulose (Avicel®; FMC;Philadelphia, Pa.) and the mixture was mixed thoroughly for about tenminutes. The mixture was then dried in an Aeromatic fluid-bed dryer(Niro Inc.; Columbia, Md.) at an inlet temperature of 65° C. The driedAvicel® excipient so prepared comprising the ferrous ion source wasmilled through a Mini-Comil 193 (Quadro Engineering; Waterloo, Ontario,Canada) with a stainless steel screen. This identical procedure wasemployed to prepare excipients comprising lactose and the ferrous ionsource. A pre-determined amount of Compound 1, the dried Avicel® orlactose excipient comprising the ferrous ion source, and crospovidone(BASF Corp.; Mount Olive, N.J.) were added to a stainless steelV-blender and blended for about 20 minutes. Magnesium stearate was thenadded and the resulting mixture was blended for an additional fiveminutes. The lubricated granulate so prepared was roll-compacted on aTF-min Roller Compactor (Vector Corporation; Marion, Iowa) utilizing aroller speed of six rpm, a screw-feeder speed of 16 rpm, and a rollerpressure of 20 kg/cm². The compacted ribbons so produced were milledwith a rotary granulator with a 20 mesh stainless steel screen. Thegranulate so produced was transferred into a four quarter V-blender andblended for five minutes. The second half portion of magnesium stearatewas then added and blended for an additional five minutes. Thelubricated granulate so produced was compressed on a rotary-type KilianT-100 tablet press (Kilian & Co.; Horsham, Pa.). Tablets were compressedat a weight of about 300 mg for 100 mg potency formulations using astandard round concave ⅜″ punch.

[0019] The tablets so prepared were stored under accelerated stabilityconditions, i.e. at 40° C. at 75% relative humidity and 50° C. at 20%relative humidity for six weeks. Reversed-phase ion pair liquidchromatography (RPLC) was then employed to separate Compound I from itsisopropyloxide (M+16) and isopropylperoxide (M+32) oxidative degradationproducts. RPLC was performed utilizing a Waters Symmetry C₈ column(Waters Instrument Co.; Milford, Mass.) 15 cm length×3.9 mm I.D. at atemperature of 40° C. using a mobile phase of 0.1 M C₈H₁₇O₃SNa in 0.05 MKH₂PO₄ (pH 3.0): acetonitrile (55:45 v/v), a flow rate of 1.0 mL/min.,and an injection volume of 20 μL at a run time of 60 minutes.

[0020] As summarized hereinbelow in Tables 1 and 2, the formation of theisopropyloxide (M+16) and isopropylperoxide (M+32) oxidative degradationby-products of Compound 1 was inhibited significantly by the addition ofthe ferrous ion source to the formulation.

[0021] As indicated in Table 1, formation of the M+16 and M+32 oxidativedegradation by-products of Compound 1 was reduced from 0.22% and 0.41%,in the samples comprising only Compound 1 and Avicel®, to 0.07% and0.04%, respectively, in the samples comprising Compound 1, Avicel®, and0.01% of ferrous ion.

[0022] Similarly, as indicated in Table 2, formation of the M+16 andM+32 oxidative degradation by-products of Compound 1 was reduced from0.16% and 0.27%, in the samples comprising only Compound 1 and lactose,to 0.06% and 0.00%, respectively, in the samples comprising Compound 1,lactose, and 0.01% of ferrous ion.

[0023] Compound 2 was similarly formulated with, inter alia, excipientscomprising about 0.01% of ferrous ammonium sulfate hexahydrate intosolid binary pharmaceutical formulations. The excipients furtherincluded microcrystalline cellulose (Avicel®), lactose, or silicifiedmicrocrystalline cellulose (Prosolv®; Penwest Pharmaceuticals;Patterson, N.Y.).

[0024] The formulations so prepared were then stored under acceleratedstability conditions, i.e. at 40° C. at 75% relative humidity and 50° C.at 20% relative humidity for six weeks. Reversed-phase ion pair liquidchromatography (RPLC) was used to separate Compound 2 from its N-oxideoxidative degradation product. RPLC was performed utilizing a WatersSymmetry C₁₈ column (Waters Instrument Co.; Milford, Mass.) 15 cmlength×3.9 mm I.D. at a temperature of 40° C. using a mobile phase ofbuffer (20 mM KH₂PO₄ (pH adjusted to 3.0 with phosphoric acid, with 0.1%octanesulfonic acid): acetonitrile (60:40 v/v), a flow rate of 1.0mL/min., and an injection volume of 10 μL at a run time of 35 minutes.

[0025] As summarized hereinbelow in Table 3, the formation of theN-oxide oxidative degradation by-product of Compound 2 was inhibitedsignificantly by the addition of the ferrous ion source to theformulations. For example, formation of the N-oxide oxidativedegradation by-product of Compound 2 was reduced from 5.07%, in theformulation comprising only Compound 2 and lactose, to 0.07% in theformulation comprising Compound 2, lactose and 0.01% of ferrous ion.Similarly, formation of the N-oxide oxidative degradation by-product ofCompound 2 was reduced from 5.50%, in the formulation comprising onlyCompound 2 and Avicel®, to 0.70% in the formulation comprising Compound2, Avicel® and 0.01% of ferrous ion. Finally, formation of the N-oxideoxidative degradation by-product of Compound 2 was reduced from 3.30%,in the formulation comprising only Compound 2 and Prosolv®, to 0.30% inthe formulation comprising Compound 2, Prosolv® and 0.01% of ferrousion. TABLE 1 Stability Results of Binary Mixture of Avicel ® andCompound 1 % M + 16 by-product % M + 32 by-product by RPLC by RPLCCompound 1 0.22% 0.41% and Avicel ® Compound 1, Avicel ® 0.07% 0.04% and0.01% Fe⁺²

[0026] TABLE 2 Stability Results of Binary Mixture of Lactose andCompound 1 % M + 16 by-product % M + 32 by-product by RPLC by RPLCCompound 1 0.16% 0.27% and lactose Compound 1, lactose and 0.06% 0.00%0.01% Fe⁺²

[0027] TABLE 3 Stability Results of Binary Mixture of Lactose, Avicel ®,or Prosolv ® With Compound 2 % Compound 2 N-Oxide by RPLC Compound 25.07% and lactose Compound 2, lactose and 0.07% 0.01% Fe⁺² Compound 25.50% and Avicel ® Compound 2, Avicel ® and 0.70% 0.01% Fe⁺² Compound 23.30% and Prosolv ® Compound 2, Prosolv ® and 0.30% 0.01% Fe⁺²

1. A method of inhibiting oxidative degradation of a pharmaceuticalformulation comprising at least one oxidation-susceptible active drugingredient which method comprises adding to said formulation anoxidation-inhibiting amount of a ferrous ion source.
 2. A methodaccording to claim 1 wherein said oxidation-susceptible active drugingredient comprises at least one amine or benzyl functional group.
 3. Amethod according to claim 1 wherein said ferrous ion source comprisesferrous sulfate, ammonium ferrous sulfate, ferrous gluconate, ferrouscitrate, ferrous fumarate, ferrous lactate, ferrous carbonate, andferrous chloride, chelated and hydrated forms thereof, and mixturesthereof.
 4. A method according to claim 3 wherein said ferrous ionsource is selected from the group consisting of ferrous sulfate,ammonium ferrous sulfate hexahydrate, and ferrous chloride.
 5. A methodaccording to claim 1 wherein said ferrous ion source comprises at leasta portion of a pharmaceutical excipient.
 6. A method according to claim1 wherein said ferrous ion source comprises from about 0.001% to about5.0% by weight of said formulation.
 7. A method according to claim 6wherein said ferrous ion source comprises from about 0.002% to about0.02% by weight of said formulation.
 8. A method according to claim 7wherein said ferrous ion source comprises about 0.01% by weight of saidformulation.
 9. A formulation comprising at least oneoxidation-susceptible active drug ingredient and an oxidation-inhibitingamount of a ferrous iron source.
 10. A formulation according to claim 9wherein said ferrous ion source comprises at least a portion of apharmaceutical excipient.
 11. A formulation according to claim 9 whereinsaid oxidation-susceptible active drug ingredient comprises at least oneamine or benzyl functional group.
 12. A formulation according to claim 9wherein said ferrous ion source comprises ammonium ferrous sulfate,ferrous sulfate, ferrous gluconate, ferrous citrate, ferrous fumarate,ferrous lactate, ferrous carbonate, ferrous chloride, chelated andhydrated forms thereof, and mixtures thereof.
 13. A formulationaccording to claim 12 wherein said ferrous ion source is selected fromthe group consisting of ferrous sulfate, ammonium ferroussulfatehexahydrate, and ferrous chloride.
 14. A formulation according toclaim 9 wherein said ferrous ion source comprises from about 0.001% toabout 5.0% by weight of said formulation.
 15. A formulation according toclaim 14 wherein said ferrous ion source comprises from about 0.002% toabout 0.02% by weight of said formulation.
 16. A formulation accordingto claim 15 wherein said ferrous ion source comprises about 0.01 % byweight of said formulation.
 17. The use of a ferrous ion source as ananti-oxidant in a pharmaceutical formulation.